Despite the advance in various therapeutic means, acute myocardial infarction (AMI) is still the leading cause of mortality in the western world. Acute myocardial infarction refers to a common clinical condition that leads to necrosis of myocardial tissue. This condition is well known in the art and is characterized by the occurrence of pain, in most cases precordial, characteristic electrocardiographic changes and an increase in plasma levels of intracellular enzymes released by the necrotic cardiac tissue such as creatinine phosphokinase and α-hydroxybutyrate dehydrogenase. AMI may be accompanied by hypotension, circulatory failure, pulmonary edema and arrhythmia. In most cases, but not exclusively, AMI results from vascular injury and thrombosis in the coronary vessels, which causes these vessels to become occluded with subsequent impaired blood flow to the jeopardized myocardium (Fuster, V. et al., 1992, New Engl. J. Med., 326:242 and 310). In most cases, the time of the occlusion of the coronary vessel can be estimated from the medical history, the course of plasma levels of intracellular heart muscle enzymes and electrocardiographic changes.
The initiating event of many myocardial infarctions (heart attacks) is rupture of an atherosclerotic plaque. Such rupture may result in formation of a thrombus or blood clot in the coronary artery which supplies the infarct zone. The infarct zone or area, as it is commonly referred to, is an area of necrosis which results from an obstruction of blood circulation. The thrombus formed is composed of a combination of fibrin and blood platelets. The formation of a fibrin-platelet clot has serious clinical ramifications. The location, degree and duration of the occlusion caused by the fibrin-platelet clot determine the mass of the infarct zone and the extent of damage.
Myocardial infarction occurs generally with an abrupt decrease in coronary blood flow to the infarct zone that follows a thrombotic occlusion of a coronary artery. The occluded artery often has been narrowed previously by atherosclerosis, and the risk of recurrent myocardial infarction persists in many patients. Ultimately, the extent of myocardial damage caused by the coronary occlusion depends upon the “territory” supplied by the affected vessel, the degree of occlusion of the vessel, the amount of blood supplied by collateral vessels to the affected tissue, and the demand for oxygen of the myocardium whose blood supply has suddenly been limited (Pasternak, R. and Braunwald, E., 1994, Acute Myocardial Infarction, Harrison's Principles of Internal Medicine, 13th Ed., pgs. 1066-77.)
Inflammation has been related both to the pathogenesis of acute myocardial infarctions and to the healing and repair following AMI. Myocardial ischemia prompts an inflammatory response. In addition, reperfusion, the mainstay of current acute therapy of AMI, also enhances inflammation. Reperfusion involves the rapid dissolution of the occluding thrombus and the restoration of blood flow to the area of the heart which has had its blood supply cut off. The presence of inflammatory cells in the ischemic myocardial tissues has traditionally been believed to represent the pathophysiological response to injury. However, experimental studies have shown that while crucial to healing, the influx of inflammatory cells into tissues, specifically macrophages which are phagocytic cells, results in tissue injury beyond that caused by ischemia alone.
Macrophages and other leukocytes infiltrate the myocardium soon after ischemia ensues. Macrophages secrete several cytokines, which stimulate fibroblast proliferation. However, the activated macrophages also secrete cytokines and other mediators that promote myocardial damage. Accordingly, the influx of macrophages into the myocardium increases myocardial necrosis and expands the zone of infarct. Thus, although the acute phase of inflammation is a necessary response for the healing process, persistent activation is in fact harmful to the infarct area as well as the area surrounding it, the so-called ‘peri-infarct zone’.
The inflammatory response that follows myocardial ischemia is critical in determining the severity of the resultant damage caused by the activated macrophages. Plasma levels of inflammatory chemotactic factors (macrophage chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1 alpha (MIP-1 alpha), have been shown to correlate with subsequent heart failure and left ventricular dysfunction (See, for example, Parissis, J. T. et al., 2002, J. Interferon Cytokine Res., 22(2):223-9). Peripheral monocytosis (an elevated number of monocytes) at two and three days after AMI is associated with left ventricular dysfunction and left ventricular aneurysm, suggesting a possible role of monocytes in the development of left ventricular remodeling after reperfused AMI (Maekawa, Y. et al., 2002, J. Am. Coll. Cardiol., 39(2):241-6). Left ventricular remodeling after acute myocardial infarction is the process of infarct expansions followed by progressive left ventricular dilation and is associated with an adverse clinical outcome. Furthermore, plasma levels of macrophage chemoattractant protein-1 (MCP-1) are elevated in patients with acute myocardial infarction. MCP-1 is induced by myocardial ischemia/reperfusion injury and neutralization of this chemokine significantly reduced infarct size.
Suppression of the inflammatory response by nonspecific anti-inflammatory composites after coronary occlusion, in several coronary occlusion/reperfusion models, was shown to reduce the infarct area (See, for example, Squadrito, F. et al., 1997, Eur. J. Pharmacol.; 335:185-92; Libby, P. et al., 1973, J. Clin. Invest., 3:599-607; Spath J. A. et al., 1974, Circ. Res., 35: 44-51). However, these nonspecific regimens are associated with adverse effects, such as interference with scar formation and healing; and, leading in some patients, to the development of aneurysm and rupture of the ventricular wall. As such, these regimens are precluded from clinical use. On the other hand, animals deficient in the anti-inflammatory cytokine interleukin-10, that suppress macrophage function, were shown to suffer from increased infarct size and myocardial necrosis in a coronary occlusion model (Yang, Z. et al., 2000, Circulation, 101:1019-1026.)
A major therapeutic goal of modern cardiology is to design strategies aimed at minimizing myocardial necrosis and optimizing cardiac repair following myocardial infarction. One object of the invention is to describe methods which minimize the deleterious effects produced by an abrupt decrease in myocardial blood flow. It is another object of the invention to describe treatments that limit damage to the myocardium and the infarct area following acute myocardial infarction.